More than two years after the experimental drugfialuridine (FIAU) killed five patients in a Phase IIclinical trial, researchers have published details of thedisastrous study in this week's New England Journal ofMedicine (NEJM).

According to the authors of the study, the FIAU trialrevealed a new type of toxic reaction _ severe andwidespread mitochondrial damage _ that "may occurinfrequently with other nucleoside analogs." One uniqueaspect of the reaction was that it continued unabated inpatients long after they had stopped taking the drug. Thedelayed onset of symptoms has prompted researchers tocall for longer follow-up periods in preclinical andclinical studies of other nucleoside-like drugs.

In an editorial, Morton Swartz, emeritus chief ofinfectious disease at Massachusetts General Hospital andchair of the Institute of Medicine (IOM) committee thatreviewed the FIAU trial earlier this year, argued thatchanges in preclinical and clinical testing proceduresshould be made to avert similar tragedies.

Specifically, Swartz called for the explicit definition of afollow-up period of at least six months for all studiesusing drugs suspected of modifying nucleic acids. He alsorecommended preclinical testing of nucleoside-like drugsin animals and cell-culture lines for their long-termeffects on nuclear, and particularly, mitochondrial DNA.Such studies would represent a more technical andexpensive approach to animal and in vitro toxicologytesting than is routinely taken by drug companies.

Finally, Swartz said that Phase II studies involvingextended treatment should always have a control arm (theFIAU trial was an open label study comparing twodifferent doses of the drug) and that data analysis fromclinical trials should be conducted on a "real-time basis"to ensure early recognition of adverse events.

FIAU Is Different From Similar Drugs

Other nucleoside analogs, such as zidovudine (AZT),didanosine (ddI) and zalcitabine (ddC), are approved inthe U.S. to treat HIV infection and have been known tocause relatively mild mitochondrial injury in somepatients. However, the authors of the NEJM studyconcluded that FIAU is fundamentally different fromthese drugs. It has a free 3' hydroxyl group that allows itto form diester bonds after incorporation into DNA. Thus,researchers have theorized that the cellular injury causedby FIAU may be due to the synthesis of defectivemitochondrial DNA, leading to reduced amounts ofmitochondrial DNA or to abnormal enzymes encoded bymitochondrial genes.

One experimental nucleoside analog currently at theforefront of AIDS drug development is 3TC (also knownas lamivudine). Glaxo Wellcome plc filed a new drugapplication (NDA) last June based on data from a pivotaltrial testing the drug as a combination therapy with AZT.The NDA is slated for review at a Nov. 6, 1995, meetingof the FDA Antiviral Drugs Advisory Committee.

3TC originally was discovered and developed by theCanadian biotechnology firm BioChem Pharma Inc.,which subsequently licensed the compound to Glaxo.According to BioChem Pharma spokeswoman ChristineLennon, 3TC has produced few side effects in repeatedlong-term testing since 1991 in thousands of patients.Lennon said that when the initial FIAU deaths werereported in 1993, researchers began to pay close attentionto the issue of mitochondrial injury. "It's old news but it'simportant news," she said. "It gave a lot of people awake-up call."

FIAU's Legacy: Lawsuits, New Regulations

The FIAU trial has spawned multi-million dollarlawsuits, has prompted the FDA to propose new adverseevent reporting requirements and has underscored therisks inherent in medical research. In addition, the trialhas been the subject of three official governmentinquiries, one commissioned by the National Institutes ofHealth (NIH), one by the FDA and one by the IOM.

In October 1994, the FDA proposed sweeping newregulations to govern adverse event reporting for drugsand biologics that were a direct result of the FIAU fiasco.Since then, the agency has received a stack of commentletters from drug companies and others engaged inclinical research that measures nearly nine inches high.Critics said the proposed rules will make the alreadytortuous process of drug development even more time-consuming and expensive. (See BioWorld Today, June15, 1995, p. 1.)

FDA spokeswoman Lenore Gelb told BioWorld Todaythat the October 1994 proposed rule remains just that: aproposal. No final rule has been published. "At this point,the issue remains open and we can't say when or if therule might become final," she said. Gelb added that, ingeneral, the more comments filed by industry and otherinterested parties, the longer FDA officials need to reviseproposed rules and study the issues.

$20M Wrongful Death Suit Still Pending

As for the plethora of lawsuits filed in the wake of theFIAU disaster (See BioWorld Today, Oct. 31, 1994),many have been quietly settled out of court though atleast one $20 million "wrongful death" suit is stillpending. Plaintiffs included the families of patients whodied in the FIAU trial, as well as patients from earlierstudies that suffered long-lasting side effects, such asperipheral neuropathy. Although BioWorld Today hasconfirmed that some plaintiffs received monetarydamages, attorneys are barred from discussing theresolution of the cases.

The suits represented an unprecedented legal challenge tothe traditional immunity of clinical trial researchers.Defendants named included Eli Lilly & Co., whichsponsored the FIAU trial and holds development andmarketing rights to FIAU, Oclassen Pharmaceuticals Inc.,a San Rafael, Calif.-based biotechnology company thatconducted early clinical studies and licensed the drug toLilly, and the U.S. government, which was involved inthe ill-fated Phase II trial via NIH researchers.

The 15-patient FIAU trial, begun in March 1993, washalted in June of that year after one patient developedsevere lactic acidosis and liver failure. Subsequently, thatpatient, as well as four others, died. Two others survivedbut only after emergency liver transplants and eightpatients suffered no severe side effects.

The Phase II trial was testing a 24-week course of FIAUtherapy for the treatment of chronic hepatitis B. Although67 patients had participated in FIAU clinical trials priorto the March 1993 trial, none had ever received more thana four-week course of FIAU. The IOM study concluded,after an extensive examination of records from the 67patients, that as many as four deaths may have beencaused by FIAU's toxic effects. If researchers had beenable to correctly attribute the earlier deaths to the drug,the tragic Phase II trial might never have been initiated. n

-- Lisa Piercey Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.